Dr. Minmin Liu and the Unit Director, Dr. Peter A. Jones, have worked closely since 2012 and have generated a significant number of high-quality publications that have had a major impact on the field of cancer epigenetics. Dr. Liu made the discovery that in cancer cells, treatment with vitamin C or G9Ai (G9A lysine methyltransferase inhibitor) synergistically enhances the effects of 5-aza-CdR, a DNA methyltransferase inhibitor (DNMTi). The underlying mechanism is through increased expression of endogenous retroviruses (ERVs) and activation of an anti-viral interferon response, which inhibits cancer cell growth and causes apoptosis. These findings sparked her interest in further exploring the roles of repetitive elements (including ERVs) in cancer immune signaling and in understanding the molecular mechanisms of their expression in cancer cells. Because her studies suggest that ERVs are important targets of epigenetic therapy, further research in this area is likely to advance the development of targeted therapies that have improved efficacy in cancer treatment. The objective of this proposal is to support Dr. Liu's career development as a research specialist in making significant contributions to Dr. Jones' established research program, which is funded by NCI. Dr. Liu is currently addressing the following questions. 1) Why are there so many mutations in chromatin modifiers, and what are the effects of these mutations on the structure of the epigenome? 2) What double-stranded RNAs (such as ERVs) are activated by 5-aza-CdR and how do these relate to cellular responses? 3) Can we design combinations of epigenetic drugs that might increase the effectiveness of 5-azanucleoside treatment? The aims for her future studies are to define the roles of ERVs in cancer immune signaling and to identify regulators for their expression. These projects will provide new insights for our understanding of the epigenome holistically and will lead toward novel strategies that increase patient response to epigenetic therapies. This award will enable Dr. Liu to have the freedom and security to advance her research in cancer epigenetics and to support the research program of the Jones group.